Cell-cell interactions are important in the development and activities of multi-cellular organisms. Stable cell-cell interactions maintain the integrity and functions of cells in tissues. More transient cell-cell interactions through multivalent ligand-receptor interaction on the cell surface underlie many aspects of immune responses, including target recognition, immune cell activation and target elimination. For example, cells of the immune systems detect foreign antigens presented on the surface of infected cells, or identify and eliminate cancer cells that exhibit aberrant cell surface proteins.
Despite decades of research efforts, cancer remains today's most pressing health concerns. Cancer treatment using small molecules had shown early promises. However, identification of small molecules with anti-cancer activities involves time-consuming and expensive screening processes. Additionally, anti-tumor small molecules often possess debilitating side effects.
Cancer originates from genetic abnormalities that cause the affected cells to behave differently at the molecular level. The molecular alterations of tumor cells can be detected, and subsequently the tumor cells can be rejected by the body's immune surveillance system. Both CD4 helper T cells and CD8 cytotoxic T cells play a pivotal role in tumor immunity. Traditionally, T cell tumor immunity has been ascribed to CD8 cytotoxic T cell. However, it has become increasingly clear that CD4 helper T cells also play a central role in tumor immunity. For example, evidence has shown that CD4 null mice were unable to mount an effective immune response to a certain form of melanoma. (Hung, K et al., 1998. The central role of CD4 T cells in the antitumor immune response. J. Exp. Med. 188, pp. 2357-2368). Additionally, both Th0 and Th1 cells have been shown to increase the activity of tumor-specific CTL clones. (Lee, K Y, et al. Immunoregulatory effects of CD4+ T helper subsets in human melanoma. Surgery 1995, 117, pp. 365-72)
CD8 T cells and natural killer (NK) cells are traditionally known as the major players in tumor immunity. The engagement of MHC class I on an antigen presenting cell (APC) with the T cell receptor (TCR) activates CD8 T cells. The activated CD8 cytotoxic T cell can directly kill the tumor cell through well characterized mechanisms. (Abbas, A. K, and Lichtman, 2005. A. H. Cellular and Molecular Immunology. Elsevier Saunders, Philadelphia, Pa.). Tumor cells often contain genetic alterations that result in reduced levels of MHC I expression to evade immune surveillance. The NK cells detect cells with reduced levels of MHC I expression and are activated by the tumor cells with altered levels of surface MHC class I. Activated NK cells release granule contents that induce apoptosis of the target tumor cells.
The anti-tumor effects of T cells are triggered by the interaction and engagement of T cells with the target tumor cells. Attempts have been made to augment tumor immunity by using bi-specific hybrid antibodies that direct immune cells to the proximity of tumor cells (Carter, P. 2001, Bispecific human IgG by design. J. Immunological Methods. 248, pp. 7-15). However, the creation of such hybrid antibodies is predicated on the availability of existing antibodies that recognize tumor cells and antibodies that recognize T cells. The knowledge of a wide variety of tumor antigens representative of different types of cancer is also required. Further, the creation and application of bi-specific antibodies faces multiple technical challenges, such as mis-pairing between immunoglobulin H- and L-chains, instability of engineered molecules, difficulty in large scale production, and potential health risk due to the intrinsic immunogenicity of antibodies. The current method is therefore poorly suited for an effective tumor immune therapy with general applicability because it is labor-intensive, unpredictable, time consuming, and costly. Thus, a better designed technology that provides a rapid, robust, and inexpensive approach for augmenting tumor immunity by promoting cell-cell interaction is needed.